Dietary restriction (DR) increases lifespan and delays the onset of age-dependent diseases. The overarching goal of this proposal is to identify the molecular mechanisms underlying the benefits of DR on longevity. The energy-sensing AMP-activated protein kinase (AMPK) is activated in response to decreased cellular energy levels, a direct consequence of DR, raising the possibility that AMPK mediates lifespan extension in response to DR. We recently showed that AMPK is required for DR to extend lifespan in worms and that AMPK phosphorylates and activates FoxO transcription factors, proteins that are known to regulate lifespan in several species. Based on recent work in which we identified genes regulated by FoxO transcription factors in response to AMPK activation, we hypothesize that the energy-sensing AMPK translates DR signals into long-term changes in gene expression programs, at least partly through the activation of FoxO transcription factors. To address the question of how AMPK regulates the extension of lifespan in response to DR, we propose the following specific aims: Aim 1. To dissect the role of the AMPK family in sensing DR signals Aim 2. To determine the molecular mechanisms by which AMPK extends lifespan A combination of genetics and biochemical approaches in Caenorhabditis elegans (C. elegans) will be used to develop these aims. Deciphering the mechanisms by which AMPK controls longevity in response to DR will increase our knowledge of the genes and the cellular responses that are important to control lifespan. Understanding the role of the AMPK-FoxO pathway in longevity in C. elegans will also provide a molecular foundation for studying the mechanisms underlying DR benefits on lifespan in mammals. PUBLIC HEALTH RELEVANCE: Dietary restriction (DR) extends lifespan and delays the onset of age-dependent diseases, including cancer and neurodegenerative disorders. Identifying the molecular basis by which DR exerts its benefits on lifespan will help uncover the important components of the DR regimen to possibly mimic the effects of DR to make it of practical use for preventing and treating age-dependent pathologies.